1. Field of the Invention
The present invention generally relates to an improved method for producing D-chiro-inositol for the treatment or prevention of insulin-resistant diabetes mellitus, and other related diseases.
2. Description of the Prior Art
As disclosed in the co-pending patent application having Ser. No. 320484, chiroinositol is an essential carbohydrate of the insulin mediator responsible for activating pyruvate dehydrogenase (PDH). In the co-pending patent applications having Ser. Nos. 320485 and 476953, it was shown that lower than normal levels of D- or L-chiro-inositol in samples of a patient's serum or urine is indicative of the patient's predisposition towards diabetes and that extremely low levels of D- or L-chiro-inositol is indicative of a patient suffering from insulin-resistant diabetes. It was suggested, in the co-pending patent application having Ser. No. 320482, that patients suffering from diabetes may in fact be incapable of synthesizing, in vivo, D-chiro-inositol. It was also postulated, as outlined in the co-pending patent application having Ser. No. 320482, that administering a therapeutic dose of D-chiroinositol to patients suffering from diabetes or that are pre-disposed to diabetes can have beneficial affects.
The methyl ester of D-chiro-inositol, D-chiro (+)-o-methyl inositol (also known as pinitol), has been isolated from the leaves of the Bougainvillea spectabilis (BVS) plant. This procedure requires repeated extractions with alcohol and water followed by drying the alcoholic extract and then extracting the dried alcoholic extract successively by hot-percolation with petroleum ether, benzene, ethyl acetate, and methanol. Pinitol is eluted as a crystalline compound having a melting point (M.P.) of 190.degree. C. The yield of pinitol after this procedure of several successive extractions is only 10%. Moreover, pinitol must then be de-esterified using hydroiodic acid (HI) to produce D-chiroinositol.
Arthur B. Anderson has disclosed methods for extracting pinitol from sugar pine (Pinus lambertina Douglas) in Industrial and Engineering Chemistry, Vol. 45, March 1953, pp. 593-96, and in TAPPI, Vol. 35, No. 5, May 1952. Schweizer et al. has disclosed that various esterified forms of chiro-inositol can be isolated from chick peas and other legumes in J. Sci. Food Agric., Vol. 29, pp. 148-54 (1978). The isolation techniques disclosed in Anderson and Schweizer et al. are also tedious, time consuming endeavors which require multiple extractions and produce relatively low yields, and they are analogous to the isolation technique discussed above in connection with the isolation of pinitol from BVS. Likewise, the isolated product obtained from the Anderson and Schweizer et al. processes must be de-esterified to produce chiroinositol
D-chiro-inositol can also be produced by the direct inversion of the three position hydroxy constituent of myo-inositol using the organic synthetic methodology described by Shen et al. in Tetrahedron Letters, Vol. 131, No. 8, pp. 1105-8 and 1109-12, 1990. Myo-inositol is not a particularly good source of D-chiro-inositol because the present synthetic methodology is very expensive.
Kasugamycin is an antibiotic compound having a chemical formula of C.sub.14 H.sub.25 O.sub.9 N.sub.3. Kasugamycin was discovered in the mid-1960s and is discussed in U.S. Pat. No. 3,358,001 to Umezawa et al. As disclosed in U.S. Pat. No. 3,607,657, to Umezawa et al., Kasugamycin can be produced by cultivating a strain of streptomyces named Streptomyces kasugaspinus. Kasugamycin is a white amorphous powder which has no definite melting point. It has been shown to be useful in medicine as a therapeutic in the treatment of Pseudomonas infections in humans and is also useful in the prevention of rice blast disease. Since kasugamycin has a very low toxicity to humans, it is ideally suited for use as an agricultural chemical. Other U.S. Patents which generally relate to kasugamycin and its use are the following: U.S. Pat. Nos. 3,681,398 to Umezawa et al, 3,856,969 to Umezawa et al., and 3,968,100 to Umezawa.